Studies in this Cutting-Edge Basic Research Award proposal would create a mouse model to assess genetic variability for in vivo physiological effects of NMDA antagonist drugs of abuse using auditory event related potentials (ERPs). Background: Abuse of NMDA receptor antagonists, such as ketamine and phencyclidine (PCP), has been recognized for many years. However, recent studies indicate that ketamine abuse has become more common among a subset of the population including people who frequent rave club parties, as well as military and medical personnel. The consequences of ketamine and PCP abuse include hallucinations, paranoia, disorganization and cognitive impairments. While many symptoms resolve within hours, others have been reported to last for many days. However, few studies have addressed genetic and other biological factors and that influence individual differences in ketamine and PCP sensitivity. Hypothesis: Animal studies with ketamine/PCP indicate that their behavioral effects and cellular toxicity are dependent on genetic background, suggesting differential vulnerability to their mechanism of action. Subanesthetic doses of ketamine/PCP have been proposed to exert their effect primarily by disrupting NMDA receptor-mediated glutamate transmission on GABAergic interneurons. This supports a hypothesis that genetic background may influence disruption of NMDA-mediated transmission on GABAergic interneurons to modulate the acute presentation and long-term sequelae of PCP/ketamine abuse. Research Project: The PI has developed a method to assess auditory ERPs in non-anesthetized mice with preliminary data demonstrating differential effects of ketamine among three inbred mouse strains. Aim 1 would determine the dose response relationship for the effects of acute ketamine administration on auditory ERPs in three inbred mouse strains. Aim 2 would then determine the differential sensitivity to effects of chronic ketamine on auditory ERPs in these three strains. Lastly, Aim 3 would determine the sensitivity to long-term changes following acute and chronic exposure to ketamine. Environment: The Stanley Center for Experimental Therapeutics in Psychiatry is a basic science laboratory within the Division of Neuropsychiatry and is part of The Center for Neurobiology and Behavior at the University of Pennsylvania. This laboratory contains all of the necessary resources to conduct the proposed studies of ketamine modulation of auditory ERPs in mice. Future Directions: Development of this model would facilitate examination of environmental, genetic and pharmacological factors that modulate the in vivo effects of ketamine and PCP. Such studies would also contribute basic knowledge regarding the neurobiological mechanisms of action, predisposition to toxicity and development of interventions directed at prevention of long-term sequelae following ketamine and PCP exposure.